Preparation of ergot and process of making same



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Patented c.luly 24, 1934 sures PATENT @FFHC Marvin R. Thompson,Baltimore, MIL, asslgnor to Abbott Laboratories, North Chicago, Ill.

No Drawing. Gontinuation of application Serial No. 407,282, November 14,1929. This application March 23, 1933, Serial No. 662,385

8 lllaims.

This invention is directed to a process for the treatment of andimproving the quality of ergot, and also directed to the ergot productresulting from such process.

Ergot is a widely known and used medicine and contains a number ofphysiologically active alkaloids and other active principles. Freshlycollected ergot, it is believed contains essentially no highly activeinjurious substances, but it has been clearly demonstrated that whenergot has been gathered for six to eight months or longer, it will befound to contain certain very toxic and highly undesirable impurities,probably produced by the decomposition in the original me= terial. Amongsuch lznown toxic substances may be listed histamine (ergarnine),tyramine, ace= tyl and other cholines, agznatine, guenido butyl amine,isoamyl amine, and others, each and all of which are; toxic andgenerally soluble in the solvents ordinarily used to extract thealkaloids and other active desirable principles oi ergot.

As all or practically all ergot appearing on the American market hasbeen gathered ior at least six months, and some of it for several years,it is to be expected that these toxic substances may sometimes occur inharmful, if no dangerous quantities in the ergot intended for and usedas a medicinal agent. As a matter of fact ex-= tensive research hasclearly demonstrated the presence of these toxic and injurioussubstances in ergot on the market, and has also demonstrated the furtherfact that such injurious sub= stances noticeably increase duringprolonged storage of ergot. It is also known that the customaryextraction with benzine, gasoline, petroleum ether, preliminarilyemployed tor the removal of the oily or fatty constituents oi ergot,does not remove these toizlc substances, and that such substances,notwithstanding known treatments appear in available preparations invarying proportions.

The method as carried out for the treatment of ergot or ergotpreparations may be generally defined in the following examples, suchbeing given, however, as specific instances for the pur poses of a clearunderstanding or" the invention and not for the purposes orcorrespondingly limiting the scope of the claims defining the invention.

Example 1.The ground up ergot may be first subjected to the customarywashing or percolation with a sumcient amount of gasoline, benzine, 0rpetroleum ether for removing the fatty or oily bodies, and to conditionthe ergot for treatment by the subsequent aqueous liquid.

This defatting treatment is not, however, absolutely necessary for thepurposes of the present method. The drug is then dried of the fatsolvent, if used, by exposure to a current of warm air or otherconventional means. The drug is then subjected to the solvent'acticn ofwater containing carbonates, lei-carbonates or hydroxides of non-toxicmetals, as soduim, potassium, calcium, or the corresponding ornmoniumcompounds. This operation may be eliected by maceration, percolation, orwashing. This method step serves to remove the undo sirable toxicsubstances, but this step, it is to be emphasized, does not remove thealkaloids or any substantial amounts of any of the useful activeconstituents of the ergot. Water alone can be used for this step, butsuch causes a slight loss of the alkaloids present in the ergot, owingto the natural slightly acid condition of the ergot.

The treatment with water or aqueous rear bonate, bicarbonate orhydroxide solution is car-= ried out at a relatively low temperature,for example, below 10 C., with a view to prevent any fermentation orputrefaction of the drugs; or,

if desired, very small amounts of preservative substances, aschloroform, carbon-tetrachloride, volatile oils, chlor-butanol, or thelike, may be added to the aqueous menstruum. When using the solublealkali metal carbonates or bi-carbonates, solutions of 1.2% strength upto 10% strength may be safely employed. When using the solublehydroxides'however, such as caustic Y soda, the concentration should notbe over 5% in any event andpreierably solutions of about 9.25% to 1.5%are employed. The carbonates and' bi-carbonates are preferred to thehydroxides, for the reason that the latter strong alkalies causedecomposition of the active agents.

It may be stated that the aqueous liquid used in this step not onlyremoves the nonspecific is then removed from the drug by washing with160 water. The residue of the extraction is preferably pressed to driveout as much of the aqueous liquid as possible, and may then be dried ata low temperature and stored for a. long period under proper condtions(such as absence of moisture and high temperatures) without thelikelihood of toxic substances being again formed therein.

The aqueous solution will of course remove certain other undesirablesubstances from the 1m ergot, such as proteins, coloring matter, etc.,and thereby materially improve the quality of the material if it is tobe used for hypodermic or other. injections, in which uses the presenceof proteins or substances other than the desirable active agents arelikely to cause disturbances in the patient. The drying operation ofthis step is not absolutely necessary and may be omitted if the drug isto be immediately used for the preparation of extracts or with otherremedies.

Following the preceding step, with or without subsequent drying, thedrug can be treated with solvents for the contained active principles.Among such serviceable solvents may be mentioned alcohol, ether,acidified alcohol, acidified water and alcohol, with or withoutglycerine or other organic solvent.

In connection with the preceding step it is to be noted that sodium orpotassium bi-carbonates can be used very efiectively and safely inremoving the toxic and inert impurities, but that the alkalinehydroxides can be used only with great danger of decomposing valuablealkaloids, thereby causing a destruction of the desirable physiologicalactivity and the natural ratio of the alkaloids, one to the other, inthe resultant product. The same danger accompanies the use of any andall of the usual high ionized alkalies. Only chemicals which are ofthemselves practically neutral, but which possess a latent alkalinityonly in the presence of an acid can advantageously be used. Sodium andpotassium bi-carbonates and to a great extent the correspondingcarbonates are such sub stances, and their use is attended bypractically no decomposition of the valuable active principles and noloss in activity during this leaching step in Example 1, or in theprecipitating step in Example 2, to be later described.

In connection with Example 1, other solvents, such as ethylene glycol,ketones such as acetone, esters such as ethyl acetate, higher alcoholssuch as butyl or amyl alcohol, or ethers, can also be used as extractivesolvents. The solvents may be acidified with a mineral or organic acid,for example, 0.5% of hydrochloric or other mineral acid, or up to 4% or5% of tartaric acid or other organic acids. These solvents shouldsubsequently be removed with water or alcohol substituted. The extractcan then be diluted to the extent desired, and is suitable for eitheroral or hypodermic administration. If it is to be used for hypodermicinjection the alcohol content and hydrogen ion (pH) concentration shouldbe suitably adjusted. Alcohol can be distilled oil, preferably underreduced atmospheric pressure and the hydrogen ion concentration can bereduced by careful addition of nontoxic alkalies. Suitablepreservatives, such as chlor-butanol, may also be added to preventdeterioration of the active principles. Any of the ergot preparationsdeveloped by this method may be further purified if desired, as inExample 2.

Example 2.Ergot preparations occurring on the market and usuallycontaining solutions of the active agents of ergot in alcohol and wateror alcohol, acid and water, usually contain more or less of theobjectionable toxic and inert substances above referred to. These can bepurified by the following treatment.

The alcohol present is preferably distilled off under reduced pressure,or, the alcohol concentration may be reduced by simple dilution toseveral times its original volume with water. The acidity is thenneutralized by the use of carbonates, bi-carbonates, or hydroxides ofnontoxic metals, as above indicated. The alkaloids and other desirableactive principles are thereby rendered insoluble and precipitated.Bi-carbonate of soda is distinctly preferably in this acidneutralization as the alkalies cause appreciable decomposition of theactive principles.

The precipitated active principles, separated i'rom the liquid byfiltration, decantation, shaking out by using an immiscible solvent(ether, etc.) and subsequently recovering the active principles byevaporation of the ether or the like, are redissolved in a suitablequantity or acidified water, alcohol, acidified alcohol and water, orother suitable solvents, and a small quantity of a preservative, such aschlor-butanol added, if desired, to prevent deterioration of thesolution.

The resulting purified preparation, or the preparations made from thepurified drug retain the greater part of their physiological activity,as shown by the tests commonly employed, as the Cook's comb test and theBroom-Clark isolated rabbit uterus test, etc.

More briefly stated, the process forming the subject matter of thepresent invention involves first, starting with powdered ergot thesubstantially complete removal of all the extractive material of ergot,except the specific alkaloids, by percolation with water treated,preferably, with sodium bi-carbonate. The specific alkaloids 01' ergotare insoluble in water or sodium bi-carbonate solution, while theobjectionable principles are completely soluble in such a solution.After complete removal of these objectionable constituents in thismanner, the drug is subjected to the solvent action of liquids in whichthe specific alkaloids oi ergot are completely soluble. This lastpercolate constitutes the improved preparation, and contains only thespecific alkaloids of ergot in their natural ratio, in solution, second,starting with conventional crude extracts of ergot, the subject matterof the present invention involves reducing the alcohol concentration ofthe extract by distillation under reduced pressure or by suitabledilution with water, neutralizing the acidity with sodium bicarbonate orother suitable weakly alkaline reagent, thus causing precipitation ofthe total alkaloids. The precipitated total alkaloids are collected byfiltration, or by shaking out with an immiscible solvent. In the lattercase the total alkaloids are obtained by evaporation of the volatileimmiscible solvent, ether, benzol, etc.

The preparation, produced as a result of the method defined, presents anew product. There is produced under the purifying process a solidproduct wherein essentially all of the undesirable toxic and inertextractives have been removed, with the only remaining extractives thoseof the therapeutically desirable active alkaloids existing in theirnatural ratio, unimpaired by drastic chemical agents. Furthermore, theenzymes responsible for the deterioration of the active principles ofthe drug have been removed. The further step of the process results in aproduct appearing as a crystal-clear solution of the total activeprinciples of ergot in their natural ratio, substantially free fromobjectionable non-specific amines, enzymes, and inert extractives, Allother liquid products 01. ergot, so far as known, which contain thetotal alkaloids nos-mes in their natural ratio, also contain thenon-specific amines, enzymes, and inert extractives, and are necessarilyunstable, their therapeutic action is slow and not dependable, andundesirable side actions result irom the toxic impurities,

All other solid products of ergot, so far as known, consist of either(1) of the total active principles contaminated with the objectionableimpurities; or (2) of one or another of the single individual isolatedalkaloids, but not in admixture in their natural ratio.

This application is filed as a continuation of my application filedNovember 14, 1929, Serial Number 407,282.

What is claimed as new, is:-

l. A process for the removal of toxic impurities from ergot, consistingin treating the ergot with water containing a material selected from a.group including carbonates, bicarbonates, or hydroxides 01' ammonium,sodium, potassium, or calcium, to thereby bring the pH to a value of notless than 7.0 and not more than 9.0, and separating the aqueous solutioncontaining the toxic and inert impurities from the residual materialcontaining the active components oi. the ergot.

2. A process which comprises crushing raw ergot and leaching the samewith an alkaline aqueous liquid which is non-injurious to the activeprinciples of ergot and in which said active principles are insoluble,to thereby remove the objectionable toxic and inert substances, andthereafter treating the solid residue of such step with organic solventsof the active principles of the ergot.

3. A process which comprises crushing raw ergot leaching the same withan aqueous solution containing a material of a group includingcarbonates, bicarbonates, or hydroxides 0! ammonium, sodium, potassium,or calcium in such proportions as to impart a pH value of 7.0 to 9.0 toavoid injury to the active principles of the ergot, separating thesolution carrying the toxic and inert impurities from the residuematerial, and treating such residue material with solvents fordissolving the active principles of the ergot.

4. A process for removing toxic andinert impurities from an ordinarycommercial extracts of ergot, consisting in diluting the extract withwater to reduce the alcohol concentration, pre-.

cipitating the desirable active principles contained in the extract witha material of a group including carbonates, bicarbonates, or hydroxidesof ammonium, sodium, potassium, or calcium, to thereby bring the pH ofthe diluted extract to a value of not less than 7.0 and not more than9.0, recovering the precipitated desirable active principles and dryingthe recovered material at a low temperature.

5. A process for removing toxic and inert impurities from ordinarycommercial extract of ergot, consisting in diluting the extract withwater to reduce the alcohol concentration, precipitating the desiredactive principles contained in the extracts with a material of a groupincluding carbonates, bicarbonates, or hydroxides of ammonium, sodium,potassium, or calcium, to bring the pH oi. the diluted extract to avalue of not less than 7.0 and not more than 9.0, recovering theprecipitated active principles of the material, and immediatelyre-dissolving said active principles in a suitable solvent, as one of agroup including acidified water, alcohol, or conventional organicsolvents.

6. An ergot product having all undesirable amines, enzymes and inertextractives eliminated said product being i'ormed by precipitating thedesired principles with a material of a group including carbonates,bicarbonates, or hydroxides of ammonium, sodium, potassium, calcium,lithium, magnesium or strontium, said precipitated active principlesbeing redissolved in a solvent to present a crystal-clear solution orthe total active principles of the ergot.

7. An ergot product having all undesirable amines, enzymes and inertextractives eliminated,

said product being formed by precipitating the desired principles with amaterial of a group including carbonates. bicarbonates or hydroxides orammonium, sodium, potassium, calcium, lithium magnesium, or strontium.8. A solid ergot product having all undesirabl amines, enzymes, andinert extractives eliminated, said product being formed by theprecipitate resulting from treatment of conventional de-alcoholizedextracts of ergot with a material of a group including carbonates,bicarbonates, or hydroxides of ammonium, sodium, potassium,calcium,.lithium, magnesium, or strontium.

MARVIN R. THOMPSON.

